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Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study meets generally accepted scientific principles, acceptable for assessment.
Objective of study:
distribution
toxicokinetics
Principles of method if other than guideline:
14 day toxicokinetic study in rats.
GLP compliance:
not specified
Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Møllegaard A/S, L1, Skensved, Denmark
- Weight at study initiation: 150 - 200 g
- Individual metabolism cages: no
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 4-6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23±1 during exposure
- Humidity (%): 70 ± 20 during exposure
- Photoperiod (hrs dark / hrs light): 10/14
Route of administration:
inhalation: vapour
Vehicle:
unchanged (no vehicle)
Details on exposure:
TYPE OF INHALATION EXPOSURE: whole body

GENERATION OF TEST ATMOSPHERE / CHAMPER DESCRIPTION
- Exposure apparatus: conical 0.7 m³ inhalation chambers with a glass front door and walls, accommodating 4 cages each containing up to 6 rats each.
TYPE OF INHALATION EXPOSURE: whole body

Dynamic exposure of anomals was performed in conically shaped 0.7 m3 steel chambers with glass front door and walls as described elsewhere (Walseth & Nilsen 1984). The concentration of hydrocarbons in the inhalation chambers was monitored automatically by on-line gas chromatography, Concentrations were measured in 15 min intervals. The injected sample was separated at 200°C on a 2m x1/8'' stainless steel column packed with GP 10% SP-2100 on Supelcoport 100/120 mesh, with helium as carrier gas. The hydrocarbons were detected by flame ionization (FID) with injector and detector temperatures of 250°. The daily mean concentration was calculated from all measurements performed after the first hour of exposure. During this first hour the concentration exceeded 95% of the steady state concentration.
Duration and frequency of treatment / exposure:
1, 3, 7, 10 and 14 days, 12 hours/day
Remarks:
Doses / Concentrations:
5.18 (day 1), 5.24 (day 3), 5.51 (day 7), 5.49 (day 10) and 5.46 (day 14) mg/L, respectively (corresponding to 987, 1000, 1051, 1047 and 1041 ppm, respectively)
No. of animals per sex per dose / concentration:
4 per exposure duration
Control animals:
no
Positive control reference chemical:
not applicable
Details on study design:
The aimed concentration was 1000 ppm. All exposures were performed at daytime for 12 hr (8 a.m. - 8 p.m.). Measurements were done on days 1, 3, 7, 10, and 14 after 12 hr exposure. Animals were one by one removed, killed, and blood and organs obtained within 3 min after removal from exposure chamber.
Details on dosing and sampling:
PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: blood, brain, perirenal fat
- Time and frequency of sampling: day 1, 3, 7, 10 and 14, within 3 min of removal from inhalation chamber
Statistics:
Student's t-test. Differences in mean concentrations between groups of unequal size were tested by Cochran t-test after comparison of variances by F-test. p<0.05 for statistical significance.
Preliminary studies:
Not performed
Details on absorption:
Not addressed.
Details on distribution in tissues:
n-Nonane demonstrated the highest concentration in blood and brain tissue on day 1 after exposure with gradually decreasing levels thereafter. In perirenal fat, a different pattern was seen with concentrations increasing significantly from day 1 to day 3, thereafter decreasing rapidly from day 7 to 14. The brain/blood concentration ratio was 11.4 and the fat/blood ratio was 113 at day 14.

In comparison with the aromatic and naphthenic hydrocarbons with which it was tested, n-nonane showed the highest accumulation potential in the brain concurrent with a low concentration in the blood. The lower solubility and lower absorption efficiency may facilitate further transportation of alkanes to the brain resulting in transient CNS effects.
Key result
Test no.:
#1
Transfer type:
blood/brain barrier
Observation:
distinct transfer
Details on excretion:
Not addressed.
Metabolites identified:
not measured

Tissue values extrapolated from graphs:

Day

1

3

7

10

14

ppm

987

1000

1051

1047

1041

Blood (µmol/L)

174

140

125

95

94

Brain (µmol/kg)

1416

1200

1200

1050

1000

Fat (µmol/kg)

12500

15980

13500

10000

7500

Conclusion:

n-Nonane was found in higher concentrations in brain and in lower concentrations in blood on day 1 after exposure. The levels in brain and blood decreased with increasing exposure days. In perirenal fat, concentrations of n-nonane were the highest compared to brain and blood. Maximum concentrations in perirenal fat was observed at 3 days of exposure and rapidly declined over the duration of the study to ½ concentration by day 14. The decline in concentration in all monitored systems suggests adaptive mechanisms with the induction of metabolizing enzymes over time.


In subsequent studies, Zahlsen et al. 1992 corroborated these observations for n-alkanes administered at lower concentration of 100 ppm for 12 hours for 3 days: low concentration in blood, relatively high concentration in brain and potential for accumulation in fat with repeated exposure up to day 3 termination.

Conclusions:
Interpretation of results: other: see conclusions below

n-Nonane was found in higher concentrations in brain and in lower concentrations in blood on day 1 after exposure. The levels in brain and blood decreased with increasing exposure days. In perirenal fat, concentrations of n-nonane were the highest compared to brain and blood. Maximum concentrations in perirenal fat was observed at 3 days of exposure and rapidly declined over the duration of the study to ½ concentration by day 14. The decline in concentration in all monitored systems suggests adaptive mechanisms with the induction of metabolizing enzymes over time.
Executive summary:

n-Nonane was found in higher concentrations in brain and in lower concentrations in blood on day 1 after exposure. The levels in brain and blood decreased with increasing exposure days. In perirenal fat, concentrations of n-nonane were the highest compared to brain and blood. Maximum concentrations in perirenal fat was observed at 3 days of exposure and rapidly declined over the duration of the study to ½ concentration by day 14. The decline in concentration in all monitored systems suggests adaptive mechanisms with the induction of metabolizing enzymes over time.

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Basic data given.
Reason / purpose for cross-reference:
reference to same study
Objective of study:
distribution
Principles of method if other than guideline:
Rats were exposed to inhalation of nonane for 8 hours. Blood and brain concentrations of nonane were monitored at the end of the exposure period.
GLP compliance:
not specified
Radiolabelling:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Mollegaard A/S, Ll. Skensved, Denmark
- Weight at exposure: 200 g ± 20 %
- Housing: The number of animals in each cage was 4 with a maximum of 4 cages in each inhalation chamber.
- Individual metabolism cages: no
- Diet (e.g. ad libitum): ad libitium except during exposure
- Water (e.g. ad libitum): ad libitium except during exposure
- Acclimation period: 4 to 6 days before the start of exposure


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22±1
- Humidity (%): 40-70
- Photoperiod (hrs dark / hrs light): 10/14
Route of administration:
inhalation: vapour
Vehicle:
unchanged (no vehicle)
Details on exposure:
TYPE OF INHALATION EXPOSURE: whole body

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Animals were kept in conically shaped 0.7 cubic metre steel chambers with glass front and walls.
- Method of holding animals in test chamber: a maximum number of 18 animals in each chamber
- System of generating particulates/aerosols: Dynamic exposure was performed by passing high oil-and dust-filtered air under pressure through 4 reservoirs of each containing 0.5 L of the test substance. At an air flow rate of 30-40 L/min an outlet concentration equal to 95% of vapour saturation was achieved. The vapour generating system was located in a water bath. Saturation concentrations of nonane at 20°C were achieved by keeping a constant temperature in the water bath of 22.5°C.
Air from the vapour generating system was introduced at the top of the exposure chamber and drained from the chamber through a perforated bottom outlet.
- Temperature, humidity, pressure in air chamber: 22±1 °C, 40-70%
Air was withdrawn from the inhalation chamber by a ventilation fan creating a negative pressure of 2-5 mm H2O on the inside of the chamber. During exposure the flow of air through the chamber (exposure and control) was 30-40 L/min, corresponding approx. to 3 air changes/hour.


TEST ATMOSPHERE
- Brief description of analytical method used:
Concentration of nonane in the inhalation chamber was monitored automatically every 15 min by on-line gas chromatography. Nonane was detected by a FID detector and quantified by a programmable integrator (Shimadzu C-R3A) which also controlled the frequency and sequence of air sampling.
Duration and frequency of treatment / exposure:
8 hours
Remarks:
Doses / Concentrations:
2414, 3560, 4438, 5280 ppm (corresponding to approx. 12.84, 18.94, 23.61, 28.09 mg/L)
No. of animals per sex per dose / concentration:
8 male rats
Control animals:
yes, sham-exposed
Positive control reference chemical:
no data
Details on study design:
The inhalation period was 8 hours at daytime during the light period. The high level exposure was performed at the maximum concentration in the air at 20 °C, i.e. saturated vapour.
Details on dosing and sampling:
The concentration of nonane was measured in blood and brain by head space gas chromatography immediately after the end of the 8 hours exposure period. Animals were removed from the chamber one by one for immediate decapitation and sample preparation. The preparation of samples was performed after standardised time schedule with less than two minutes between decapitation and isolation of blood and the brain samples from each animal.

The concentration of nonane in blood and brain were determined immediately after the termination of the 8 hours exposure (table 2). The corresponding blood/air and brain/air concentration ratios were also given (table 2). With increasing dose levels, the concentration of nonane in blood and brain as far as possible was increased. In comparision to other alkanes (n-C10 to n-C13), the lower alkanes were found in higher concentrations in blood and brain than the higher alkanes, both absolutely and when correcting for the different air concentrations (data not shown).

Table 1: Concentration of nonane in inhaled air.

A period of 1 hour was needed to achieve steady state air concentration.

chamber concentration [ppm ± SD] (measured at 15 min intervals; generated at 21.6 °C)
 5280 ± 77* (generated at 22.5 °C)
 4438 ± 319*
 3560 ± 17
 2414 ± 7

* saturation level

Table 2: Concentration of nonane in rat blood and brain at the end of an 8 hours exposure period and the corresponding blood/air and brain/air concentration ratios. All concentrations represent mean ± SD of 5 animals surviving the exposure.

 Blood concentration [mg/L]  Brain concentration [mg/kg]  Blood/air ratio  Brain/air ratio  dose level [ppm]
 238*  1136*  8.6  41.3  5280
 109 ± 52  919 ± 67  4.7  39.5  4438
 135 ± 19  590 ± 34  7.2  31.7  3560
 57 ± 6  314 ± 35  4.5  24.3  2414

* Concentration measured in one animal that died 0.5 hour before the end of the exposure period.

Conclusions:
Interpretation of results: other: see conclusions below

In comparision to other alkanes (n-C10 to n-C13), the lower alkanes were found in higher concentrations in blood and brain than the higher alkanes, both absolutely and when correcting for the different air concentrations.
Executive summary:

In comparision to other alkanes (n-C10 to n-C13), the lower alkanes were found in higher concentrations in blood and brain than the higher alkanes, both absolutely and when correcting for the different air concentrations.

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Basic data given.
Objective of study:
absorption
Principles of method if other than guideline:
The comparative rates of uptake of 19 hydrocarbon (including nonane) vapours by rats were determined by a dual-column gas chromatography method.
GLP compliance:
not specified
Radiolabelling:
no
Species:
rat
Strain:
other: F344/N
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Lovelace ITRI colony
- Age at study initiation: 12 to 15 weeks
- Weight at study initiation: mean 298 g
- Housing: Before exposure, animals were housed in polycarbonate cages (2 animals/cage) with hardwood chip bedding and filter caps.
- Individual metabolism cages: yes/no
- Diet (e.g. ad libitum): AM. Food (Lab Blox, Allied Mills, Chicago, IL, USA); ad libitum
- Water (e.g. ad libitum): water from bottles with sipper tubes; ad libitium


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 to 22.2
- Humidity (%): 20 to 50
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
inhalation: vapour
Vehicle:
unchanged (no vehicle)
Details on exposure:
TYPE OF INHALATION EXPOSURE: nose only

The exposure apparatus, exposure procedures, and method for handling data were described in detail by Dahl et al., 1987 (Amer Ind Hyg Assoc J 48:505-510)

The vapour was pumped at 400 mL/min from a Teflon supply bag through one sampling loop of a dual-column gas chromatograph, past the nose of a rat confined in a nose-only exposure tube, through the second sampling loop of the dual column gas chromatograph and, finally, into an exhaust bag.
The amount of hydrocarbon vapour absorbed was calculated from the output of the gas chromatograph and the flow rate past the rat´s nose. Rat exposures were preceded by a 10-15 min pre-exposure equilibration/calibration period without a rat in the system.


Duration and frequency of treatment / exposure:
80 min for 5 consecutive days (totally 450 min)
Remarks:
Doses / Concentrations:
on day 1: 1 ppm
on day 2: 10 ppm
on day 3: 100 ppm
on day 4: 1000 ppm
on day 5: 5000 ppm
See also "any other information on materials and methods".
No. of animals per sex per dose / concentration:
at 100 ppm: 10 male rats (not further specified)
Control animals:
not specified
Positive control reference chemical:
no data
Details on study design:
All animals were exposed for 80 min/day for 5 consecutive days with escalation of vapour concentration daily.
Details on dosing and sampling:
During the exposures (80 min/day), respiratory and gas chromatographic data were collected at 1 min intervals.
Statistics:
The calculation of vapour uptake from gas chromatography data see attached document.
Details on absorption:
Values of the uptake of inhaled nonane vapours (of two independent experiments) were 8.9 ± 1.5 nmol/kg/min/ppm (N=10) and 9.4 ± 0.6 nmol/kg/min/ppm (N=10). The values are given for uptake during minutes 60 to 70 from start of exposure.
Conclusions:
Interpretation of results: bioaccumulation potential cannot be judged based on study results

Taking into account all data of the report, a number of trends relating uptake to chemicals properties were observed. Among these, highly volatile hydrocarbons are less well-absorbed than less volatile hydrocarbons; unsaturated compounds are better absorbed than saturated ones; and branched hydrocarbons are less well-absorbed than unbranched ones. These trends can be used to predict relative uptake rates within classes of hydrocarbons.
Executive summary:

Taking into account all data of the report, a number of trends relating uptake to chemicals properties were observed. Among these, highly volatile hydrocarbons are less well-absorbed than less volatile hydrocarbons; unsaturated compounds are better absorbed than saturated ones; and branched hydrocarbons are less well-absorbed than unbranched ones. These trends can be used to predict relative uptake rates within classes of hydrocarbons.

Endpoint:
dermal absorption in vitro / ex vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study meets generally accepted scientific principles, acceptable for assessment.
Justification for type of information:
A discussion and report on the read across strategy is given as an attachment in IUCLID Section 13.
Reason / purpose for cross-reference:
read-across: supporting information
Principles of method if other than guideline:
Guidance for conduct of the in vitro dermal kinetic experiments was posted in the United States FR, April 26, 2004 (Volume 69, Number 80), pages 22402-22441, "In vitro dermal absorption rate testing of certain chemicals of interest to the occupational safety and health administration".
GLP compliance:
not specified
Radiolabelling:
yes
Species:
other: in vitro human skin model
Strain:
other: in vitro human skin model
Sex:
not specified
Details on test animals or test system and environmental conditions:
not applicable
Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Duration of exposure:
up to 60 min
Doses:
infinite dose: 1200 µL/cm2
10 min: 20 µL
60 min: 20 µL
No. of animals per group:
in vitro human skin model
Control animals:
no
Details on in vitro test system (if applicable):
see "any other information on materials and methods"
Signs and symptoms of toxicity:
not examined
Dermal irritation:
yes

The flux values for Normal-Heptane and the 10 and 60 min short-term absorption values (the quantity of chemical remaining in the skin plus that portion that had penetrated the skin was detected in the receptor fluid) were 63.2 µg/cm2/h, 113 µg/cm2/h (for the 10 min flux) and 22.1 µg/cm2/h (for the 60 min flux). Therefore, 10 min flux value for Normal-Heptane (based on both the amount in the skin and the receptor solution) was greater than the flux measured in a similar manner over 60 min.

Skin integrity measurements were taken before and after each experiment. All reporting laboratories (Normal-Heptane: Hask, DuPont Haskell Laboratory, USA) either used tritiated water permeability or electrical resistance (impedance) to confirm skin integrity; for consistency and to ease comparisons, all tritiated Kp values were converted to electrical impedance values expressed in kilo-ohms (k-ohms). A ratio of post- to pre-test impedance of "1" indicates that the skin barrier did not change over the course of the experiment. In the Kp experiments, skin exposed to Normal-Heptane had a damage ratio of 0.57, confirming that approx. 43% of the skin barrier function was lost due to exposure to Normal-Heptane. The barrier properties for the skin in the short-term experiments were given as the ratios of 0.90 for 10 min and 0.88 for 60 min.

Recovery of the applied dose, based on liquid scintillation count data when the radioactive chemical form was spiked into the non-radiolabeled chemical, was 95.5% (for the Kp experiment), 54.0% (for the 10 min experiment) and 110.0% (for the 60 min experiment).

At the end of the Kp experiment, the portion of Normal-Heptane in the skin (0.01%) was less than the portion in the receptor solution (0.12%). The portion of Normal-Heptane in the donor solution (wash) was 95.4%. In contrast to the Kp experiment, the skin (0.14%) retained a larger percentage of Normal-Heptane following a 10 min exposure. The portion of Normal-Heptane in the donor solution (wash) was 6.84% at 10 min. The greater portion of the applied dose remaining in the skin at 10 min suggests that partitioning into the skin from the donor solution is the driver of penetration with this brief exposure. After the 60 min experiments, there was also a larger percentage of n-heptane in the receptor solution (0.12%) than in the skin (0.06%). The increased proportion of Normal-Heptane detected in the receptor solution illustrates and confirms the movement of the chemical from the skin into the receptor solution.

Conclusions:
Under the test conditions, Normal-Heptane was able to penetrate the skin. During prolonged exposure, the penetration of the skin was aggravated, since the exposure to n-heptane simultaneously reduced skin barrier function.
Executive summary:

Under the test conditions, Normal-Heptane was able to penetrate the skin. During prolonged exposure, the penetration of the skin was aggravated, since the exposure to Normal-Heptane simultaneously reduced skin barrier function.

Description of key information

Short description of key information on bioaccumulation potential result:
See toxicokinetics, metabolism and distribution.


Short description of key information on absorption rate:
Under dermal in vitro test conditions, normal-heptane was able to penetrate the skin. During prolonged exposure, the penetration of the skin was aggravated, since the exposure to normal-heptane simultaneously reduced skin barrier function. Similar properties are expected for nonane.


Due to the experimental setup, e. g. undepletable reservoir of test substance and therefore absence of any evaporation, the dermal penetration factors reported by Fasano and McDougal (2008) are very conservative. In contrast, when using a diffusion cell, which is a more realistic setup for volatile substances like hydrocarbon solvents, dermal penetration rates of 0.1 µg/cm2/h and 0.0005 µg/cm2/h were obtained for heptane and octane, respectively (Tsuruta et al., 1982).

Key value for chemical safety assessment

Additional information

Zahlsen et al. (1990) initially exposed male rats to 1000 ppm of nonane vapor 12 hours/day, for 1, 3, 7, 10, or 14 days to evaluate distribution in different tissues. The concentration of nonane was measured by head space gas chromatography in blood, brain and perirenal fat. Nonane was found in higher concentrations in brain and in lower concentrations in blood on day 1 after exposure. The levels in brain and blood decreased with increasing exposure days. In perirenal fat, concentrations of nonane were the highest compared to brain and blood. Maximum concentrations in perirenal fat was observed at 3 days of exposure and rapidly declined over the duration of the study to ½ concentration by day 14. The decline in concentration in all monitored systems suggests adaptive mechanisms with the induction of metabolizing enzymes over time. The lower absorption efficiency of nonane in the blood and its lower volatility may facilitate the transportation of nonane to the brain resulting in reported transient CNS effects. In a subsequent study, Zahlsen et al. (1992) corroborated these observations for nonane administered at the lower concentration of 100 ppm, 12 hours/day, for 3 days: Low concentration in blood, relatively high concentration in brain and potential for accumulation in fat with repeated exposure up to day 3 were observed.

In comparison with the aromatic and naphthenic hydrocarbons which were also tested, nonane showed the highest concentrations in the brain concurrent with a low concentration in the blood. The lower solubility and lower absorption efficiency may facilitate further transportation of alkanes to the brain resulting in transient CNS effects.

The inhaled uptake of n-nonane vapors was explored by Dahl et al. (1988) in male rats exposed for 5 consecutive days, 80 min/day with escalation of vapor concentration daily (from 1 ppm up to 5000 ppm). During the exposures, respiratory and gas chromatographic data were collected at 1 min intervals. Uptake of inhaled nonane vapors (of 2 independent experiments, n = 10) was 8.9 ± 1.5 nmol/kg/min/ppm and 9.4 ± 0.6 nmol/kg/min/ppm. The values are given for uptake during minutes 60 to 70 from start of exposure of the experiment.

Nilson et al. (1988) exposed rats to nonane vapor (2414, 3560, 4438, 5280 ppm) for 8 hours. The concentration of nonane was monitored in blood and brain by head space gas chromatography at the end of the exposure period. With increasing dose levels, the concentration of nonane in blood and brain was increased. In comparision with other n-alkanes (n-C10 to n-C13), the lower n-alkanes accumulated to a higher extent in blood and brain than the higer n-alkanes both absolutely and when correcting for the different air concentrations.

 

In general, nonane is readily absorbed and distributed through the body. Furthermore it is readily metabolized and excreted in urine and expired as CO2. Based on read-across from the structurally related compound normal-heptane within a category approach, there appears to be a very low rate of metabolism to potentially neurotoxic gamma diketones in rats. Under dermal in vitro test conditions, normal-heptane was able to penetrate the skin. During prolonged exposure, the penetration of the skin was aggravated, since the exposure to normal-heptane simultaneously reduced skin barrier function. Similar properties are expected for nonane.

Discussion on bioaccumulation potential result:

See toxicokinetics, metabolism and distribution.

Discussion on absorption rate:

There are no dermal absorption data available on nonane. However, there are reliable data available for a structural analogue. Thus, read-across was conducted based on an analogue approach.

Fasano and McDougal (2008) described the procedures for determination of a permeability coefficient (Kp) and two short-term dermal absorption rates at 10 and 60 min. The flux values for normal-heptane and the 10 and 60 min short-term absorption values (the quantity of chemical remaining in the skin plus that portion that had penetrated the skin was detected in the receptor fluid) were 63.2 µg/cm2/h, 113 µg/cm2/h (for the 10 min flux) and 22.1 µg/cm2/h (for the 60 min flux). Therefore, the 10 min flux value for normal-heptane (based on both the amount in the skin and the receptor solution) was greater than the flux measured in a similar manner over 60 min.

Skin integrity measurements were taken before and after each experiment. A ratio of post-to pre-test impedance of "1" indicates that the skin barrier did not change over the course of the experiment. In the Kp experiments, skin exposed to normal-heptane had a damage ratio of 0.57, confirming that approx. 43% of the skin barrier function was lost due to exposure to normal-heptane. The barrier properties for the skin in the short-term experiments were given as the ratios of 0.90 for 10 min and 0.88 for 60 min. At the end of the Kp experiment, the portion of normal-heptane in the skin (0.01%) was less than the portion in the receptor solution (0.12%). The portion of normal-heptane in the donor solution (wash) was 95.4%. In contrast to the Kp experiment, the skin (0.14%) retained a larger percentage of normal-heptane following a 10 min exposure. The portion of normal-heptane in the donor solution (wash) was 6.84% at 10 min. The greater portion of the applied dose remaining in the skin at 10 min suggests that partitioning into the skin from the donor solution is the driver of penetration with this brief exposure. After the 60 min experiments, there was also a larger percentage of normal-heptane in the receptor solution (0.12%) than in the skin (0.06%). The increased proportion of normal-heptane detected in the receptor solution illustrates and confirms the movement of the chemical from the skin into the receptor solution. Under the test conditions, normal-heptane was able to penetrate the skin. During prolonged exposure, the penetration of the skin was aggravated, since the exposure to normal-heptane simultaneously reduced skin barrier function.